Blood stem cell transplantation following high dose chemotherapy is standard of care and potentially curative for aggressive forms of lymphoma. However, this treatment regimen is limited by severe toxicity and life-threatening complications due to delayed recovery of the blood system and vascular related damage of multiple organs.
This brings the number of clinical trials funded by CIRM to 86.
The Board awarded $15,000,000 to Dr. Paul Finnegan and Angiocrine Bioscience to test AB-205, human endothelial cells engineered to express a pro-survival factor.
Prior data suggest that, in the setting of chemotherapy and stem cell transplantation, AB-205 cell therapy can accelerate the recovery of the blood system and protects from toxicity by enhancing the recovery from vascular damage. AB-205 is being studied in a Phase 3 trial in adults with lymphoma undergoing high-dose chemotherapy and autologous blood stem cell transplant.
“If successful, this approach can overcome hurdles to the success of chemotherapy and blood stem cell transplantation for the treatment of advanced blood cancer,” says Dr. Maria T. Millan, President and CEO of CIRM. “This Phase 3 trial is the culmination of preclinical research and the initial clinical trial previously funded by CIRM.”
Lymphoma is the most common blood cancer and one of the most common cancers in the United States, accounting for about 4% of all cancers according to the American Cancer Society and the 6th most commonly diagnosed cancer among men and women in California. It is estimated that there will be 89,010 new cases of lymphoma and 21,170 lymphoma related deaths in the US in 2022 alone. In California, it is estimated that there will be over 9,250 new cases of lymphoma with over 2,100 deaths.
“Angiocrine Bioscience is honored to be awarded this grant from CIRM to support our AB-205 Phase 3 trial,” commented Angiocrine CEO Dr. Paul Finnegan. “CIRM has been an instrumental partner in our development of AB-205, a novel therapeutic that acts on the patients’ endogenous stem cell niches. The grant award will considerably aid in our effort to bring forth a solution to the unmet need of transplant-related complications.”
Spina bifida is a birth defect that occurs when the spine and spinal cord don’t form properly and can result in life-long walking and mobility problems for the child, even paralysis.
Now, UC Davis has released more details about the clinical trial and the babies born after receiving the world’s first spina bifida treatment combining surgery with stem cells. The story was featured in BBC News and The Sacramento Bee.
The first phase of the trial is funded by a $9 million grant from the California Institute for Regenerative Medicine.
The one-of-a-kind treatment, delivered while a fetus is still developing in the mother’s womb, could improve outcomes for children with this birth defect.
A Decade’s Work
“I’ve been working toward this day for almost 25 years now,” said Dr. Diana Farmer, the world’s first woman fetal surgeon, professor and chair of surgery at UC Davis Health and principal investigator on the study.
In previous clinical trial, Farmer had helped to prove that fetal surgery reduced neurological deficits from spina bifida. Many children in that study showed improvement but still required wheelchairs or leg braces.
Farmer recruited bioengineer Dr. Aijun Wang to help take that work to the next level. Together, they researched and tested ways to use stem cells and bioengineering to advance the effectiveness and outcomes of the surgery.
Farmer, Wang and their research team have been working on their novel approach using stem cells in fetal surgery for more than 10 years. Over that time, animal modeling has shown it is capable of preventing the paralysis associated with spina bifida.
Preliminary work by Farmer and Wang proved that prenatal surgery combined with human placenta-derived mesenchymal stromal cells, held in place with a biomaterial scaffold to form a “patch,” helped lambs with spina bifida walk without noticeable disability. When the team refined their surgery and stem cells technique for canines, the treatment also improved the mobility of dogs with naturally occurring spina bifida.
The CuRe Trial
When Emily and her husband Harry learned that they would be first-time parents, they never expected any pregnancy complications. But the day that Emily learned that her developing child had spina bifida was also the day she first heard about the CuRe trial, as the clinical trial is known.
Participating in the trial would mean that she would need to temporarily move to Sacramento for the fetal surgery and then for weekly follow-up visits during her pregnancy.
After screenings, MRI scans and interviews, Emily received the news that she was accepted into the trial. Her fetal surgery was scheduled for July 12, 2021, at 25 weeks and five days gestation.
Farmer and Wang’s team manufactured clinical grade stem cells—mesenchymal stem cells—from placental tissue in the UC Davis Health’s CIRM-funded Institute for Regenerative Cures. The lab is a Good Manufacturing Practice (GMP) Laboratory for safe use in humans. It is here that they made the stem cell patch for Emily’s fetal surgery.
During Emily’s historic procedure, a small opening was made in her uterus and they floated the fetus up to that incision point so they could expose its spine and the spina bifida defect.
Then, the stem cell patch was placed directly over the exposed spinal cord of the fetus. The fetal surgeons then closed the incision to allow the tissue to regenerate. The team declared the first-of-its-kind surgery a success.
On Sept. 20, 2021, at 35 weeks and five days gestation, Robbie was born at 5 pounds, 10 ounces, 19 inches long via C-section.
For Farmer, this day is what she had long hoped for, and it came with surprises. If Robbie had remained untreated, she was expected to be born with leg paralysis.
“It was very clear the minute she was born that she was kicking her legs and I remember very clearly saying, ‘Oh my God, I think she’s wiggling her toes!’” said Farmer. “It was amazing. We kept saying, ‘Am I seeing that? Is that real?’”
Both mom and baby are at home and in good health. Robbie just celebrated her first birthday.
The CuRe team is cautious about drawing conclusions and says a lot is still to be learned during this safety phase of the trial. The team will continue to monitor Robbie and the other babies in the trial until they are 6 years old, with a key checkup happening at 30 months to see if they are walking and potty training.
“This experience has been larger than life and has exceeded every expectation. I hope this trial will enhance the quality of life for so many patients to come,” Emily said. “We are honored to be part of history in the making.”
Read the official release from UC Davis Health here.
With funding support from the California Institute for Regenerative Medicine (CIRM), Cedars-Sinai investigators have developed an investigational therapy using support cells and a protective protein that can be delivered past the blood-brain barrier. This combined stem cell and gene therapy can potentially protect diseased motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis, a fatal neurological disorder known as ALS or Lou Gehrig’s disease.
In the first trial of its kind, the Cedars-Sinai team showed that delivery of this combined treatment is safe in humans. The findings were reported in the peer-reviewed journal Nature Medicine.
What causes ALS?
ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. About 6,000 people are diagnosed with ALS each year in the U.S., and the average survival time is two to five years.
The disease results when the cells in the brain or spinal cord that instruct muscles to move—called motor neurons—die off. People with the disease lose the ability to move their muscles and, over time, the muscles atrophy and people become paralyzed and eventually die. There is no effective therapy for the disease.
Using Stem Cells to Treat ALS
In a news release, senior author Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, says using stem cells shows lots of promise in treating patients with ALS.
“We were able to show that the engineered stem cell product can be safely transplanted in the human spinal cord. And after a one-time treatment, these cells can survive and produce an important protein for over three years that is known to protect motor neurons that die in ALS,” Svendsen says.
Aimed at preserving leg function in patients with ALS, the engineered cells could pave the way to a therapeutic option for this disease that causes progressive muscle paralysis, robbing people of their ability to move, speak and breathe.
The study used stem cells originally designed in Svendsen’s laboratory to produce a protein called glial cell line-derived neurotrophic factor (GDNF). This protein can promote the survival of motor neurons, which are the cells that pass signals from the brain or spinal cord to a muscle to enable movement.
In patients with ALS, diseased glial cells can become less supportive of motor neurons, and these motor neurons progressively degenerate, causing paralysis.
By transplanting the engineered protein-producing stem cells in the central nervous system, where the compromised motor neurons are located, these stem cells can turn into new supportive glial cells and release the protective protein GDNF, which together helps the motor neurons stay alive.
Ensuring Safety in the Trial
The primary goal of the trial was to ensure that delivering the cells releasing GDNF to the spinal cord did not have any safety issues or negative effects on leg function.
In this trial, none of the 18 patients treated with the therapy—developed by Cedars-Sinai scientists and funded by CIRM—had serious side effects after the transplantation, according to the data.
Because patients with ALS usually lose strength in both legs at a similar rate, investigators transplanted the stem cell-gene product into only one side of the spinal cord so that the therapeutic effect on the treated leg could be directly compared to the untreated leg.
After the transplantation, patients were followed for a year so the team could measure the strength in the treated and untreated legs. The goal of the trial was to test for safety, which was confirmed, as there was no negative effect of the cell transplant on muscle strength in the treated leg compared to the untreated leg.
Investigators expect to start a new study with more patients soon. They will be targeting lower in the spinal cord and enrolling patients at an earlier stage of the disease to increase the chances of seeing effects of the cells on the progression of ALS.
“We are very grateful to all the participants in the study,” said Svendsen. “ALS is a very tough disease to treat, and this research gives us hope that we are getting closer to finding ways to slow down this disease.”
The Cedars-Sinai team is also using the GDNF-secreting stem cells in another CIRM-funded clinical trial for ALS, transplanting the cells into a specific brain region, called the motor cortex that controls the initiation of movement in the hand. The clinical trial is also funded by CIRM.
The California Institute for Regenerative Medicine (CIRM) remains committed to funding research and clinical trials to treat ALS. To date, CIRM has provided $93 million in funding for research to treat ALS.
Read the original source release of the study here.
Explaining science is hard. Explaining stem cells, which have their very own unique complexities, can be even more of a challenge, especially when communicating with a non-scientific audience.
That’s why when we received this blog submission from a CIRM SPARK Program intern through UCSF’s High School Intern Program (HIP) explaining stem cells in a simple, straightforward way using Legos, we knew we had to share it with our readers.
The first thing to know about stem cells is that there is not just one kind. In fact, there are many different types of stem cells, each with very different potential to treat disease. There are various types of stem cells, including pluripotent, embryonic, adult, and iPSC (induced pluripotent stem cell).
Stem cells also have the potential to become other kinds of cells in the body. For example, embryonic stem cells can become many other kinds of cells, whereas adult stem cells, such as in fat, can only become bone or cartilage.
Now, the fun part! Here’s what the student shared in their prize-winning SPARK Program blog submission.
If someone were to ask me what stem cells are in a simple and perhaps figurative way now, I would say that stem cells are just like Legos. Legos are special building-blocks that are in a blank or default-like state, but can be something greater and unique on its own later on.
Similarly, stem cells are called “unspecialized cells” because they are yet to be “specialized” or become a certain type of cell. They can be a blood, brain, heart, and basically all types of cells respectively, with little to no exceptions. Moreover, not all Legos are built the same. Some can be regular block-shaped, while some can be circular or even triangular. Therefore, this limits Legos’ abilities to a certain degree. Similarly, not all stem cells are necessarily the same.
With just the right amount and type of Legos, you can easily assemble and build a house, a car, or whatever you could possibly think about. Similarly, the possibilities are endless with stem cells as well, which is why it’s truly a promising and key aspect in regenerative medicine today.
Bravo! In addition to creating a unique way of explaining stem cells during their internship, the student also learned how to differentiate the different types and sources of stem cells from one another through hands-on experience at a world-renowned institution.
The student added, “My newly-found interest in regenerative medicine and stem cells is definitely something that I’m looking forward to with great passion and knowledge moving forward.”
To learn more about CIRM’s internship programs, visit our website. To read another prize-winning blog submission from a SPARK intern, click here.
Science is hard. Explaining complex science to non-scientists is SUPER hard. But explaining science to non-native English speakers presents a whole new set of challenges.
I would know. I’m a first-generation immigrant whose highly-educated parents arrived in their new home—the United States—a tad too late to become fluent in its native tongue. I’ve also had the unique experience of participating in a clinical trial using stem cells—a topic which my family still has trouble grasping.
I still remember the day of my accident, which left me paralyzed from the chest down. My mother came into my room to cheerfully tell me that there was “something” that would “help me walk” again. Those “something” were human embryonic stem cells. The “help me walk” part was doctors simply explaining the potential of the treatment. In her frazzled mind, she could hardly understand Farsi, much less English. Being told that I was a candidate to participate in a stem cell trial somehow translated into being cured.
And she kept looking for the magic bullet. Countless internet searches revealed all sorts of clinics and wellness centers that offered a cure to just about any disease imaginable. My mom wondered, “Were these the same stem cells from my daughter’s trial? Maybe they are even better since they are curing so many folks!”
I tried my best to explain but there was always something missing in translation. I found that troubling. The language barrier made it so difficult to make informed decisions. I couldn’t imagine being a non-native English speaker and learning about such a complicated matter in a language I hadn’t yet mastered.
After all, stem cells are a topic that concerns the people of the world, not just certain countries or certain people speaking only in certain languages.
Dr. Paul Knoepfler would know. And not just because the statement comes straight from him. Paul is a stem cell scientist at UC Davis (full disclosure, we have funded some of his work). His blog, The Niche, is one of the longest-running blogs about regenerative medicine and an especially great resource for those without a science background.
More importantly, in 2021 Dr. Knoepfler launched SCOPE, an outreach effort to make available on the internet a basic page of facts about stem cells in as many languages as possible. What started with “Stem Cells in Spanish” has quickly transformed into a stem cell white paper now available in 35 different languages!
Naturally, I wasted no time and sent the Farsi version to my parents and the French one to my francophone mother-in-law. And it isn’t just me who is finding this information useful. Dr. Knoepfler says, “SCOPE has been a big hit and as the number of languages has grown, the number of page views of my white paper ‘What are stem cells?’ in languages besides English has skyrocketed. For example, just our Stem Cells in Spanish page has received over 680,000 views as of the first half of 2021, while our Indonesian page has over 300,000 views and our Arabic page has a quarter of a million. We are getting readers from all over the world who appreciate reading about stem cells in their own languages.”
We spend around one third of our life sleeping—or at least we should. Not getting enough sleep can have serious consequences on many aspects of our health and has been linked to high blood pressure, heart disease and stroke.
A study by the American Sleep Apnea Association found that some 70 percent of Americans report getting too little sleep at least one night a month, and 11 percent report not enough sleep every night. Over time that can take a big toll on your mental and physical health. Now a new study says that impact can also put you at increased risk for eye disease.
The study published in the journal Stem Cell Reports, looked at how sleep deprivation affects corneal stem cells. These cells are essential in replacing diseased or damaged cells in the cornea, the transparent tissue layer that covers and protects the eye.
Researchers Wei Li, Zugou Liu and colleagues from Xiamen University, China and Harvard Medical School, USA, found that, in mice short-term sleep deprivation increased the rate at which stem cells in the cornea multiplied. Having too many new cells created vision problems.
They also found that long-term sleep deprivation had an even bigger impact on the health of the cornea. Sleep-deprived mice had fewer active stem cells and so were not as effective in replacing damaged or dying cells. That in turn led to a thinning of the cornea and a loss of transparency in the remaining cells.
The findings suggest that sleep deprivation negatively affects the stem cells in the cornea, possibly leading to vision impairment in the long run. It’s not clear if these findings also apply to people, but if they do, the implications could be enormous.
California researchers from UCLA and colleagues have created a first-of-its-kind roadmap that traces each step in the development of blood stem cells in the human embryo, providing scientists with a blueprint for producing fully functional blood stem cells in the lab.
The research, published in the journal Nature, could help expand treatment options for blood cancers like leukemia and inherited blood disorders such as sickle cell disease, said UCLA’s Dr. Hanna Mikkola, who led the study.
Blood stem cells, also called hematopoietic stem cells, can make unlimited copies of themselves and differentiate into every type of blood cell in the human body. For decades, doctors have used blood stem cells from the bone marrow of donors and the umbilical cords of newborns in life-saving transplant treatments for blood and immune diseases.
However, these treatments are limited by a shortage of matched donors and hampered by the low number of stem cells in cord blood.
Researchers have long sought to create blood stem cells in the lab from human pluripotent stem cells, which can potentially give rise to any cell type in the body. But success has been elusive, in part because scientists have lacked the instructions to make lab-grown cells become self-renewing blood stem cells rather than short-lived blood progenitor cells, which can only produce limited blood cell types.
“Nobody has succeeded in making functional blood stem cells from human pluripotent stem cells because we didn’t know enough about the cell we were trying to generate,” said Mikkola.
A New Roadmap
The new roadmap will help researchers understand the fundamental differences between the two cell types, which is critical for creating cells that are suitable for use in transplantation therapies, said UCLA scientist Vincenzo Calvanese, a co–first author of the research, along with UCLA’s Sandra Capellera-Garcia and Feiyang Ma.
“We now have a manual of how hematopoietic stem cells are made in the embryo and how they acquire the unique properties that make them useful for patients,” said Calvanese, who is also a group leader at University College London.
The research team created the resource using new technologies that enable scientists to identify the unique genetic networks and functions of thousands of individual cells and to reveal the location of these cells in the embryo.
The data make it possible to follow blood stem cells as they emerge and migrate through various locations during their development, starting from the aorta and ultimately arriving in the bone marrow. Importantly, the map unveils specific milestones in their maturation process, including their arrival in the liver, where they acquire the special abilities of blood stem cells.
The research group also pinpointed the exact precursor in the blood vessel wall that gives rise to blood stem cells. This discovery clarifies a longstanding controversy about the stem cells’ cellular origin and the environment that is needed to make a blood stem cell rather than a blood progenitor cell.
Through these insights into the different phases of human blood stem cell development, scientists can see how close they are to making a transplantable blood stem cell in the lab.
A Better Understanding of Blood Cancers
In addition, the map can help scientists understand how blood-forming cells that develop in the embryo contribute to human disease. For example, it provides the foundation for studying why some blood cancers that begin in utero are more aggressive than those that occur after birth.
“Now that we’ve created an online resource that scientists around the world can use to guide their research, the real work is starting,” Mikkola said. “It’s a really exciting time to be in the field because we’re finally going to be seeing the fruits of our labor.”
During a game in 2018, Alex Smith suffered a compound fracture that broke both the tibia and fibula in his right leg. The gruesome injury aside, the former 49ers quarterback soon developed life-threatening necrotizing fasciitis — a rare bacterial infection — that resulted in sepsis and required him to undergo 17 surgeries.
In a battle to save his life and avoid amputating his leg, doctors had to remove a great deal of his muscle tissue leading to volumetric muscle loss (VML). When Smith returned to the field after nearly two years of recovery, many called his comeback a “miracle”.
Skeletal muscle is one of the most dynamic tissues of the human body. It defines how we move and can repair itself after injury using stem cells. However, when significant chunks of muscle are destroyed through severe injury (e.g. gunshot wound) or excessive surgery (like that of Smith’s), VML overwhelms the regenerative capacity of the muscle stem cells.
Despite the prevalence of these injuries, no standardized evaluation protocol exists for the characterization and quantification of VML and little is understood about why it consistently overwhelms the body’s natural regenerative processes. Current treatment options include functional free muscle transfer and the use of advanced bracing designs.
However, new research from the University of Michigan (U-M) may have just discovered why tissues often fail to regenerate from traumatic muscle loss injuries.
When researchers from U-M collaborated with partners at Georgia Tech, Emory University and the University of Oregon to study VML injuries in mice, they found that that sometimes post-injury immune cells become dysregulated and prevent stem cell repair. In VML injuries that don’t heal, neutrophils — a type of white blood cell — remain at the injured site longer than normal meaning that they’re not doing their job properly.
In addition, researchers found that intercellular communication between neutrophils and natural killers cells impacted muscle stem cell-mediated repair. When neutrophils communicated with natural killer cells, they were essentially prompted to self-destruct.
The findings suggest that by altering how the two cell types communicate, different healing outcomes may be possible and could offer new treatment strategies that eventually restore function and prevent limb loss. The team of researchers hope that better treatments could mean that recovery from VML injuries is no longer considered a “miracle”.
As if that wasn’t enough Jan is part of the team helping guide UC Davis’ efforts to expand its commitment to diversity, equity and inclusion using a variety of methods including telemedicine, to reach out into rural and remote communities.
She is on the Board of several enterprises, is the editor of the journal Stem Cells and, in her copious spare time, has dozens of aquariums and is helping save endangered species.
So, it’s no wonder we wanted to chat to her about her work and find out what makes her tick. Oh, and what rock bands she really likes. You might be surprised!
Advance World Class Science, Deliver Real World Solutions, Provide Opportunity for All.
These comprise the themes of our bold 5-year Strategic Plan. Since its launch less than two months ago, we have hit the ground running. Under the second and third strategic themes, we have already received ICOC approval for 2 concepts: Alpha Clinics Network Expansion and COMPASS educational program. We are now working on the execution of our first theme.
As indicated in our Strategic Plan, we strongly believe advancing world class science relies on collaborative research that leverages collective scientific knowledge. To that end, we have organized the virtual CIRM CNS Consortium Workshop (click for the agenda and see registration details below) to help us gather feedback from a panel of experts about the best approach for promoting a culture of collaboration.
The vision for this workshop was informed by multiple layers of stakeholder discussions and input that started even prior to the passage of Proposition 14. A quick walk down memory lane reminds us of CIRM’s early and deliberate effort to identify areas of opportunity for promoting a paradigm shift with a “team science” approach, especially in the context of complex diseases such as those affecting the CNS:
In 2019, we organized Brainstorming Neurodegeneration, a workshop where broad stakeholder input was received about the benefits and bottlenecks of developing a consortium approach where genomics and big data, novel stem cell models, and patient data could be collectively leveraged to advance the field of neurodegenerative research in a collaborative manner.
In 2020, just before the passage of Prop 14 and based on input from the 2019 workshop, we already had our eyes on target: the future of collaborative research is in sharable data, and sharing petabytes or more of data requires a collaborative data infrastructure. To better understand the status and bottlenecks of knowledge platforms that could leverage data sharing, we brought together a panel of experts at our 2020 Grantee Meeting. We were encouraged to learn that our laser-focused approach for promoting knowledge sharing was right on target and the panelists suggested that CIRM has a great opportunity to promote a paradigm shift in this area.
In early 2021, immediately after the passage of Prop 14 and building upon our previous conversations, we formed a Strategic Scientific Advisory Panel comprising a distinguished group of national and international scientists in the stem cell field. Once again, we were advised to expand sharable resources (especially in the context of stem cell modeling), bring more attention to complex diseases such as neurodegenerative and neuropsychiatric disorders, and facilitate knowledge sharing.
In mid 2021, as we were forming our Strategic Plan based on the above input, we pressure-tested our paradigm-shifting vision in a Town Hall and further gathered feedback from California stakeholders about their needs. Again, all arrows pointed to shared resources and data as critical elements for accelerating research.
Finally, in late 2021, just before the launch of our Strategic Plan, we organized a Data Biosphere Advisory Committee to advise us on ways to facilitate collaborative knowledge sharing. Here, we explored various models for leveraging and/or generating a data infrastructure in which CIRM-funded data could be managed and shared. The main outcome of this meeting was a recommendation to organize a workshop to test the feasibility and approach for generation of a CIRM knowledge platform. The Committee concluded that CIRM is uniquely positioned to contribute a wealth of data to the broader scientific community. A knowledge platform would provide an avenue for data sharing and collaboration with other groups that are dedicated to accelerating progress in the development of therapies, especially for CNS disorders.
We were walking on solid ground! In December of 2021, paralleling the input we had received from experts and stakeholders, we launched our 5-year Strategic Plan with the goal of advancing world class science by promoting a culture of collaboration.
To deliver on this goal, CIRM’s approach is to build the infrastructure (and we don’t mean bricks and mortar) that organizes and democratizes data through:
A network of shared resources labs that facilitate validation and standardization to support California regenerative medicine researchers
A data infrastructure where CIRM-funded data can be shared and external datasets leveraged to maximize real-world impact
We have held a virtual CNS Consortium Workshop on February 24th and 25th where we explored the development of these two resources through the deployment of a consortium and starting in the CNS space as a use case. While the discussions at the workshop centered on the CNS, the shared resources labs will be implemented across cell types and organs. The Data Infrastructure is intended to be a global resource for data sharing and fostering a culture of open science for all CIRM grantees—and the world. The complete workshop agenda can be found here.
Watch video recordings of Day 1 and Day 2 of the CNS workshop.